GSK3965193 in chronic hepatitis B: a PAPD5/7 RNA destabilizer dropped for bepirovirsen

What was tried

GSK3965193 is an oral small-molecule inhibitor of the non-canonical poly(A) RNA polymerases PAPD5 and PAPD7. NCT05330455 was a four-part, randomized, double-blind, placebo-controlled study with an actual enrollment of 74 participants. Parts 1, 2A, and 2B evaluated single and repeat doses and a food effect in healthy participants. Part 3 evaluated GSK3965193 monotherapy in people living with chronic hepatitis B. Part 4 was designed to test GSK3965193 in combination with bepirovirsen, an antisense oligonucleotide that targets HBV transcripts. The primary outcomes were safety and tolerability across the parts. The study was terminated with the posted reason "The study was terminated as a strategic decision," and an actual primary completion date of May 19, 2025 (ClinicalTrials.gov, NCT05330455).

The biological hypothesis

Chronic hepatitis B affects more than 250 million people, and hepatitis B surface antigen plays a central role in maintaining viral persistence (Liu et al., Journal of Virology 2021). PAPD5 and PAPD7 are host poly(A) polymerases that stabilize HBV RNA through the viral post-transcriptional regulatory element. Inhibiting them destabilizes HBV RNA, which lowers surface antigen production. Genetic work using the chemical probe AB-452 showed that PAPD5 carries the dominant role in protecting the viral poly(A) tail, with PAPD7 acting as a second layer; AB-452 reduced surface antigen by 0.94 log in cell models (Liu et al., Journal of Virology 2021).

The appeal of GSK3965193 was an oral host-directed agent that could be paired with bepirovirsen. Bepirovirsen degrades HBV transcripts directly, so combining a host RNA-stability inhibitor with a transcript-targeting oligonucleotide was meant to push functional cure rates higher than either alone. This is a host-factor strategy rather than a genetically supported one. The Open Targets v4 association between PAPD5 and chronic hepatitis B is approximately 0.008, which is expected for a host dependency factor that has no human genetic link to the disease.

What actually happened

The early parts read out cleanly on safety. Across all dosed cohorts in Parts 1 through 3, the posted results record zero serious adverse events and zero deaths, in both healthy participants and people with chronic hepatitis B (ClinicalTrials.gov results posting, NCT05330455). Single-dose, repeat-dose, food-effect, and monotherapy parts all completed.

Part 4, the combination of GSK3965193 with bepirovirsen, enrolled no participants before the study closed. The results posting lists the Part 4 combination groups at zero at risk. The defining question of the program, whether adding a PAPD5/7 inhibitor to bepirovirsen raises functional cure, was never tested in humans. GSK framed the broader move as going all-in on bepirovirsen and removing one potential functional-cure asset from the hepatitis B portfolio (FierceBiotech, 2025).

Failure mechanism, best guess

This was a portfolio decision, not a safety or efficacy stop. The mechanistic context explains why the decision was rational. Bepirovirsen had by this point shown a functional cure in roughly one in five patients in two Phase 3 trials, 20 percent in B-Well 1 and 19 percent in B-Well 2 at week 72, against zero on placebo (Hou et al., New England Journal of Medicine 2026). With a lead asset delivering a defined and registrable benefit, the marginal value of an oral add-on that had not yet generated combination data was lower than the cost of running it.

The PAPD5/7 class also carries documented safety liabilities that raise the bar for a single-agent add-on. A related next-generation destabilizer, AB-161, was discontinued after male reproductive toxicity findings in dogs, and the same program flagged dose-dependent sensory nerve conduction effects at high exposures, though those remained within normal ranges (Lam et al., Viruses 2024). A host-directed agent that must reach high liver exposure to work, that has no human genetic validation, and whose class has tripped on neurological and reproductive signals is a hard internal sell once the lead antisense asset succeeds on its own.

How to prevent this next time

Two quantitative tools would have framed the combination decision before Part 4 was designed.

First, a Bayesian posterior probability of success for the combination, evaluated at the monotherapy interim and integrating the surface-antigen pharmacodynamic signal against a prior set by bepirovirsen monotherapy:

PP(success)=∫θ​P(final success∣θ,interim data)⋅π(θ∣interim data)dθ

If the monotherapy surface-antigen decline did not move the posterior for incremental combination benefit above a preset threshold, Part 4 should not have been opened. Second, an explicit power calculation against the bepirovirsen base rate. To detect a rise in functional cure from 20 percent to 30 percent with 80 percent power at a two-sided alpha of 0.05 requires on the order of 290 participants per arm, which is far beyond a Part 4 add-on cohort. Stating that arithmetic in advance shows that the combination question needed a dedicated, adequately sized study, not an exploratory tail on a Phase 1 program. A competitive landscape red-team would have added the class history of RNA-destabilizer discontinuations to the same decision.

The single highest leverage change would have been to size the combination question as its own powered trial against the bepirovirsen functional-cure base rate, rather than appending it as Part 4, so that the program either earned a real readout or was cut before enrolling a cohort that could never answer the question.

What this means for similar programs

The Claidex Mechanism Risk Score for PAPD5 in this run is 30 out of 100, in the yellow band. The genetic deficit component is near maximal at 14.9 of 15, which reflects the near-zero Open Targets association expected for a host factor. Host-directed antiviral targets will routinely score high on genetic deficit, so the score should be read as a flag to lean harder on pharmacodynamic and combination evidence, not as a verdict on the biology. The practical lesson is that host RNA-stability inhibitors for HBV live or die on combination data, and that data has to be generated in a study built to read it.

Open questions

Did GSK3965193 monotherapy lower hepatitis B surface antigen in the Part 3 patients, and by how much relative to the 0.94 log seen preclinically for AB-452? Would the combination with bepirovirsen have added benefit over bepirovirsen alone, and is that increment large enough to justify a powered trial? Does any PAPD5-selective inhibitor avoid the neurological and reproductive signals that have followed the dual PAPD5/7 chemotype?

Sources

1. • ClinicalTrials.gov, NCT05330455 (official title, four-part randomized double-blind design, actual enrollment 74, terminated, "The study was terminated as a strategic decision," primary completion May 19, 2025, results posting showing zero serious adverse events across dosed cohorts and zero enrollment in the Part 4 combination). https://clinicaltrials.gov/study/NCT05330455 - Liu F, et al. Host poly(A) polymerases PAPD5 and PAPD7 provide two layers of protection that ensure the integrity and stability of hepatitis B virus RNA. J Virol.

2. [DOI]( - Lam AM, et al. Preclinical antiviral and safety profiling of the HBV RNA destabilizer AB-161. Viruses.

3. [DOI]( - Hou J, et al. Phase 3 results of bepirovirsen treatment for chronic hepatitis B virus infection. N Engl J Med.

4. [DOI]( - Cremer J, et al. B-Clear Phase 2b study design: establishing the efficacy and safety of bepirovirsen in patients with chronic hepatitis B virus infection. Adv Ther.

5. [DOI]( - FierceBiotech, report that GSK dropped one potential functional cure for hepatitis B to focus on bepirovirsen (2025). https://www.fiercebiotech.com/biotech/gsk-removes-one-potential-functional-cure-hep-b-it-goes-all-bepirovirsen - Open Targets Platform v4, PAPD5/TENT4B (ENSG00000121274) to chronic hepatitis B (EFO_0004239) association approximately 0.008. https://platform.opentargets.org/target/ENSG00000121274.